Polyamines and Hypusine in Type 1 Diabetes Pathogenesis

University Of Chicago, Chicago IL

Investigators

Linked publications & trials

Abstract

ABSTRACT The pathogenesis of type 1 diabetes (T1D) involves complex intercellular interactions in the pancreatic microenvironment, where endocrine, exocrine, and immune cells drive early inflammatory responses. Macrophages are among the earliest immune cells to infiltrate the islets, initiating a dialog with β cells that activates adaptive immune responses, promoting autoimmunity and β-cell loss. Our recent work identified polyamines, small organic molecules involved in cellular growth and stress responses, and hypusine, a polyamine-derived modification unique to the translation factor eIF5A, as critical regulators of mRNA translation and inflammation in β cells. eIF5A requires hypusination for its activity and influences specific mRNA translation linked to inflammatory pathways. As polyamine and hypusine biosyntheses can be modulated by diet or small molecules, they offer real-world therapeutic targets to modify T1D progression. We hypothesize that the polyamine biosynthetic pathway in early T1D orchestrates post-transcriptional inflammatory responses in β cells. In the following Aims, this renewal application will leverage new findings, innovative animal models, and cutting-edge technologies to test this overarching hypothesis: Aim 1: Expose the pivotal role of β-cell ornithine decarboxylase (ODC) in the onset of T1D. Aim 2: Decipher how hypusine modification shapes β-cell inflammation and drives T1D progression. Aim 3: Reveal how β-cell polyamine metabolism modifies the inflammatory response in early T1D. Whereas T1D is an autoimmune disease, therapies exclusively targeting the immune system have seen variable success. Recent clinical successes using drugs that block inflammation and stress pathways more broadly suggest a need to revise therapeutic approaches to T1D. Collectively, this study will significantly advance our knowledge of how polyamine biosynthesis and hypusine modification scale inflammatory responses, β-cell function, and survival in early T1D. Through these aims, we will uncover regulatory pathways that could serve as novel therapeutic targets to preserve β-cell mass and function, addressing critical gaps in current strategies for T1D prevention.